Response to Vertebral Artery Dissection Study:
Synopsis Paper by Smith et al. Published in May 13, 2003Issue of Neurology

The recent publication by Smith et al. in Neurology addressing vertebral artery dissection [1] represents another episode of regrettable studies which, despite serious flaws which raise
substantial questions as to their internal validity, go at great lengths to
selectively disparage the advisability of performing cervical manipulations
as a means of patient care while obscuring the larger picture. [2-6]
By this I refer both to the failure to fully present the well-documented
benefits of this procedure as well as the equally well-chronicled risks
of alternatives to cervical manipulation—including the use of
medications which is so deeply entrenched in our society as to be obviously
far more prevalent than any applications of manipulation. The fact that
Smith’s study has been so extensively and immediately propagated in the
printed and televised media (in contrast to the many investigations which
have supported cervical manipulations with no reports of substantial
side-effects [7-30]) represents a major disservice to the American
public and threatens their access to the best available options in
healthcare.

This critique will be discussed from two
vantage points, in terms of both internal flaws and its analysis in the
larger context.

INTERNAL FLAWS:

Sampling and time frame issues:
To begin, there is no indication that the 151
dissection cases were randomly identified; only the control patients
were so chosen. The fact that some demographic features of the two groups
(such as age or dimensions of the arteries involved) differ implies a more
basic and global characteristic pertaining to arterial dissections that lies
outside cervical adjustments (a point to be discussed in detail below
regarding spontaneous arterial dissections). This would seem to be
particularly true since the number of patients in which spinal manipulative
therapy (SMT) has been reported to occur within 30 days is just 7,
compared to 3 in the control group. The differential of just 4
individuals between the two groups is a paltry number indeed upon which to
base association—let alone any hint of causality over the extended period
of 30 days. The fact that two patients actually experienced a stroke or
transient ischemic attack (TIA) immediately following SMT is clearly more
compelling—but even here the authors fail to make a distinction between
stroke and TIA (far more benign). The fact that strokes could happen at the
time of SMT but not necessarily reflect it as a risk factor will be
discussed below.

Exclusion of iatrogenic cases:
To one’s amazement, the authors excluded a
larger number of patients (8) due to "iatrogenic dissection with or
without stroke" than actually were listed as having a dissection within
30 days of spinal manipulative therapy (7). In addition to making the low
number of dissection cases within 30 days of SMT appear even more absurd,
the authors raise the more serious question as to exactly what had caused
the "iatrogenic dissections" in the first place. By most common
definitions, "iatrogenic" is thought to have been brought on by medical
interventions, a point to be discussed in more detail below.

Lack of a control population:
This study bases its conclusions only upon
the association of a single observation (presence of vertebral artery
dissection) with previous events recalled by the patient. There are no
baseline (control) readings to accompany this. One could argue that without
a control hospital laboratory finding (e.g., elevated blood urine
creatinine or presence of an arterial artery occlusion), the frequencies of
possible precipitating events prior to the primary finding (presence of
arterial artery dissection) are meaningless. By the reasoning put forth in
this study, we would be forced to the rather strange conclusion that
patients who recall cervical manipulation prior to their yielding elevated
urine creatinine (for example) could be used as evidence that this form of
intervention is necessarily associated with the aberrant blood
chemistry levels obtained.

Incorrect identification of precipitating
factors to vertebral artery (VA) dissection:
Other than "SMT," the authors have
produced no indication that cervical manipulations were administered
to every patient listed, so that their attempts to link VA dissections and
manipulation become that much more problematic. Until an actual relationship
is struck between the location, actual number of adjustments, and vertebral
dissections is given, and until some light can be shed on the mechanisms
which could produce this result, any speculation of causality of
manipulation and arterial dissection gleaned from the data in this study
must be greeted with only the most extreme skepticism.

Furthermore, the authors appear to have given
little consideration to the fact that cerebrovascular accidents appear to be
a cumulative rather than traumatic events. This fact is emphatically
driven home by the fact that no less than 68 everyday activities have
been implicated in disrupting cerebral circulation. [31-33] Among
the activities listed, 18 (childbirth, interventions by surgeon or
anesthetist during surgery, calisthenics, yoga, overhead work, neck
extension during radiography, neck extension for a bleeding nose, turning
the head while driving a vehicle, archery, wrestling, emergency
resuscitation, star gazing, sleeping position, swimming, rap dancing,
fitness exercise, beauty parlor events, and Tai Chi) have actually been
associated with vascular accidents but are decidedly non-manipulative [Attachment
1]. [33]

The risk of fatal stroke following cervical
manipulation has been assessed in an exhaustive systematic literature review
of many sources to be 3 per 10 million manipulations, [34] or about
0.00025%. [35] The mortality rate from stroke in the general
population in 1992-93 was 0.00057%, which raises the possibility that the
death rate from stroke in the general population could conceivably be
higher than that amongst chiropractic patients. [36]

Given the frequency of significant
consequences from cervical manipulations (6 per 10 million manipulations, or
0.0006%), [34] and given the many lifestyle activities shown above
to trigger cerebrovascular accidents, it would seem nearly impossible—as
this study has done—to attribute the VA dissections reported at indefinite
time periods following chiropractic manipulation to the latter. This
association, based on a vague recollection of the patient of events in the
past, cannot be counted upon to have definitively identified spinal
manipulation as a causative event. Identifying the chiropractor in
this association is even more problematical, as will be shown immediately
below.

Undetermined identification of caregiver:
Did the 7 cases of VA dissection attributed
to cervical manipulation in the study actually follow manipulation by a
licensed chiropractor? There is no validation of this fact in the
study as reported. The actual number of iatrogenic complications
specifically ascribed to chiropractic has been shown to be significantly
overestimated due to the fact that the practitioner actually involved is in
many cases a nonchiropractor. Rather, a major portion of these
accidents have occurred at the hands of an individual with inadequate
professional training but incorrectly represented in the medical literature
as a chiropractor. One particular review is alarming in that it suggests
that for many years chiropractors have been over-represented (possibly in a
systematic manner) in the literature as having brought on VAs. [37,38]

ANALYSIS IN THE LARGER CONTEXT:

Comparative safety:
Risks are inherent in every medical procedure
or lifestyle activity that we encounter. In terms of interventions of the
spine, chiropractic has been shown to be many orders of magnitude safer
than medication or surgery. Assuming that each patient receives an average
of 10 manipulations in treatment, [61] death rates following
cervical manipulation calculate to anywhere between 1/100-1/400 the
rates seen in the use of non-steroidal anti-inflammatory drugs (NSAIDs) for
the same condition. [35,39] Death rates from lumbar spine operations
have been reported to be 300 times higher than the rate produced by
cerebrovascular accidents in spinal manipulation; [40,41] for
cervical surgeries, recent death rates have been estimated to be 700-fold
greater. [40] As Rome has pointed out, [31] risks for
"virtually all" medical procedures ranging from the taking of
blood samples, [42] use of vitamins, [43] drugs, [43]
"natural" medications, [44] and vaccinations [45]
are routinely accepted by the public as a matter of course.

How risks are interpreted is another
matter. The VA rate for chiropractic as described above, while extremely
low, does represent a challenge to be improved upon. On the other hand, as
Rome points out, [31] such phenomena as (i) patient informed
consent, (ii) "low and acceptable rates of complications"
stated in a policy by the Australian College of Ophthalmologists, [46]
or (iii) "trading off" risks of surgeries and stroke as stated in
a recent study of endarterectomies [47] all attest to the fact that
certain levels of risk have been habitually accepted in our society until
improvements can be made. Why should chiropractic be singled out as having
an unacceptable risk?

In his distinction of specific provider types
associated with cerebrovascular accidents, Terrett has identified 34 deaths
associated with manipulation over 61 years worldwide. [37] For the
sake of comparison, 12,000 deaths per year from unnecessary surgery, 7,000
deaths per year from medication errors in hospitals, about 80,000 deaths per
year from nosocomial infections in hospitals, and 106,000 deaths per year
from nonerror, adverse effects of medications have been recently reported
with regard to conventional medicine. [48-50] These data are
presented simply to prevent our losing perspective on the entire issue of
risk/benefit ratios raised by the study published in Neurology. [1]

This discussion would not be complete without
considering "acceptable" lifestyle risks, which should be
common knowledge if we are to evaluate the safety of any healthcare
intervention—chiropractic or otherwise. Attachment 2 from the study
of Dinman [51] clearly indicates that the risk of death per person
per year in many of the activities that we accept as normal and engage in
are for the most part many orders of magnitude greater than those seen in
serious VA complications following chiropractic manipulation. Once again, we
must be skeptical if cervical chiropractic manipulation seems to have been
singled out as a particularly conspicuous and noxious threat to our
livelihood.

Actual forces exerted upon the VA:
From a mechanistic viewpoint, the most direct
means of assessing the effects of spinal manipulative therapy upon the
integrity of the VAs would be to directly measure how the forces anticipated
during manipulations might be transmitted through the various skeletal and
soft-tissue layers of the cervical milieu to the region of the VA, and how
such forces compare to the limits of arterial integrity assessed by
deliberately stretching the VA until it ruptures. Such a study was recently
accomplished at the University of Calgary upon the VAs excised from
unembalmed postrigor patients who had died within the past 72 hours.

In this investigation, the distal C0-C1 and
proximal C6-subclavian loops of the VAs were exposed and fitted with a pair
of piezoelectric ultrasonic crystals. Strains between each crystal pair were
recorded during range of motion testing, diagnostic tests, and a variety of
procedures employed in spinal manipulation. Afterwards, the VA was dissected
and strained on a materials testing machine until mechanical failure
occurred. For manipulation, the elongations of the C0-C1 and C6-subclavian
artery segments of the VA were 6.2% and 2.1% respectively. For normal head
rotation, on the other hand, these elongations were respectively 12.5% and
4.8%. The elongations of these same regions needed to reach VA failure were
53.1% and 62.3% respectively. Two conclusions are readily apparent: (i) the
values measured during spinal manipulative therapy were less than
those recorded during range of motion and diagnostic testing; and (ii) the
VA strains measured during spinal manipulation were less than 1/9 those
needed to achieve arterial failure. [52]

The implications of this study shed
considerable light upon the controversy regarding VADs and spinal
manipulation. First it is evident that the forces experienced during spinal
manipulation are virtually an order of magnitude below those needed to
produce an arterial failure in a single event. Secondly, it is apparent that
routine neck maneuvers during the assessments (rather than the
manipulations) registered greater forces in the region of the VAs. This
immediately raises the possibility that spontaneous rather than
induced cerebrovascular accidents (CVAs) are likely to occur in the VA, an
issue which will be explored in depth in the following section.

There are a number of significant cautionary notes that must be sounded to this study, however:

The portion of the artery most commonly
involved in VA dissections associated with spinal manipulation (C1-C2, as
pointed out earlier) was not measured; rather, the entire VA was used to
obtain mechanical failure points; [53]

Stretch by tensile forces rather than
compression by combined forces (particularly at the C2 foramen, proposed to
be the actual force causing damage during manipulation [53]) was
measured, which may not reflect the suspected type of artery deformation
occurring in patients;

The strain created to the thrust side VA
when the neck is fully rotated contralaterally, representing the most
forceful manipulation, was not measured; [53]

The ranges of motion from the 80-99-year
old cadavers would be expected to be more restricted than those more typical
of younger patients seen in chiropractic offices, limiting the strains on
the VAs that were measured by the researchers and perhaps not representative
of those seen in actual practice; [52]

There were wide variations in force ranges
(4-18N) and of strains (31%-75%); [52]

Preparing the arterial specimens in
ultrasound gel may have artificially increased their flexibility;

One may question whether the overall
arterial failures observed bear compelling resemblance to the intimal
tearing experienced in vivo during arterial dissections; and finally

Since arterial dissections may well
represent the culmination of multiple arterial insults as outlined in
the ensuring text, it is necessary that this experiment be repeated to
assess arterial integrity after dozens and perhaps hundreds of applied
stretches to the VA.

Spontaneous arterial dissections:
The most compelling information that needs to
be brought forward to bring the debate about cervical manipulations onto a
level playing field pertains to the fact that a significant number and most
likely the majority of VADs happen to be spontaneous cervical artery
dissection (sCADs). As demonstrated in numerous reports addressing both the
frequency of occurrence of VADs and their association with virtually any
activity associated with turning the head should reduce the utility of
attributing strokes to cervical manipulations to virtually an academic
exercise.

Prevalence:
As shown in Attachment 3, the annual
incidence of spontaneous VADs in hospital settings has been estimated to
occur at the rate of 1-1.5 per 100,000 patients. [54] The
corresponding VAD incidence rate in community settings has been reported to
be twice as high. [55,56] Using an estimated value of 10 from the
literature to represent an average number of manipulations per patient per
episode, [61] it becomes apparent that the proposed exposure rate
for CVAs attributed to spinal manipulation is equivalent to the spontaneous
rates for cervical arterial dissections as reported. [54-56] If the threat of
stroke or stroke-like symptoms is to be properly assessed, therefore, at
least half our attention needs to be directed toward the spontaneous events
instead of primarily or solely upon spinal manipulation.

Association of homocysteine and arterial fragility:
For over 30 years, the amino acid
homocysteine has been implicated as a key component of atherosclerotic
disease. [62-70] More direct observations point toward the
disruption of the structures of collagen and elastin in the arterial wall:

In
the majority of skin biopsies taken from patients with cervical arterial
dissections, irregular collagen fibrils and elastic fiber fragmentations
have been found. [71]

Homocysteine activates metalloproteinases [71] and serine elastases, [72]
directly or indirectly leading to the decrease in vitro of the
elastin content of the arterial wall. The opening and/or enlargement of
fenestrae in the medial elastic laminae would be expected to lead to the
premature fragmentation of the arterial elastic fibers and degradation of
the extracellular matrix. [71,72]

Homocysteine has been shown to block aldehydic groups in elastin, inhibiting
the cross-linking needed to stabilize elastin. [73]

The
cross-linking of collagen may also be impaired by homocysteine. [74]

Endothelium-dependent and flow-mediated vascular dilation is impaired in
individuals with elevated levels of homocysteine. [70]

In
cell culture experiments, addition of homocysteine into the medium induces
cell detachment from the endothelial cell monolayer. [75]

Yet even a tighter coupling between sCADs and
increased amounts of homocysteine have been shown by the following
observations:

Patients
undergoing sCADs are more than three times as likely as asymptomatic
patients to yield plasma homocysteine levels exceeding 12 micromoles/L. They
are also more than twice as likely to have elevated homocysteine as patients
experiencing ischemic strokes without arterial dissection. [76]

A
genetic defect in humans involving tetrahydrofolate reductase, the enzyme
which produces the methyl-donating cofactor required to convert homocysteine
to methionine, is associated with elevations in the rates of sCADs. [76]
This metabolic block would be expected to cause homocysteine to accumulate
intracellularly. [79]

The striking association of homocysteine with
sCAD raises the possibility that a relatively simple diagnostic test is at
hand for determining patients at risk for sCAD and who would accordingly be
advised to avoid cervical manipulation.Until recently, the gold
standard methodology for determining plasma homocysteine has been high
pressure liquid chromatography, gas chromatography, and mass spectrometry. [80-82]
Fortunately, this cumbersome technology has recently been correlated with a
much simpler enzyme conversion immunoassay (EIA). [83] An even more
rapid assay method by means of an automated analyzer is also available,
requiring only microliter amounts of reagent and sample. [84] This
essentially means that homocysteine levels can be determined in any number
of clinical reference laboratories already established to measure blood
analytes.

To date, the assessment options for
vertebrobasilar artery risk each have significant drawbacks and as a whole
have been unable to identify any particular factor that is useful for
screening. [85,86] Provocation tests in particular are problematic
in that in several aspects they replicate the risks associated with cervical
manipulation by requiring the placement of the head and neck in extreme
extension and rotation [87] False negative findings compared to
angiograms have been reported; [88] reliability and validity have
not been reliably tested; [85] and the suggestion has been made that
these tests be de-emphasized. [89] In the midst of this disorder,
determining homocysteine levels as a predictor of arterial fragility seems
to be a plausible, rapid and inexpensive procedure that is no more invasive
than a routine blood glucose determination.

CONCLUSIONS:

Thus it would appear that the tearing of the
arterial wall in a dissection is both cumulative and spontaneous:
cumulative in that repeated, low-grade insults to the artery would most
likely be required to yield a dissection; and spontaneous in that these more
minor impositions occur by dint of any number of self-imposed maneuvers as
well as any by a practitioner—making it extremely difficult if not
impossible to distinguish between the two. Finally, spontaneous dissections
appear to correlate with the fragility of the arterial wall, which may be
attributable to inborn errors of metabolism and may be detectable by means
of a homocysteine assay.

Regarding those studies mentioned above which
appear to discredit the wisdom of cervical manipulation, [1-6]
there
appear to be a number of common fallacies:

(i) They fail to disclose that
the majority of vertebrovasilar accidents (VBAs) are spontaneous,
cumulative, or caused by factors other than spinal manipulation;

(ii) They
fail to disclose the potential benefits of the procedure, violating medicine’s
own ethic of accurately reporting true risk-benefit ratios;

(iii)
They fail to place the risks of manipulation in the context of those
produced by other medical treatments or lifestyle activities;

(iv) They fail
to indicate the actual frequency of manipulations administered;

(v) They
fail to account for the possibility that patients undergoing CVAs are
reported more than once;

(vi) They fail to report the rates of CVAs
following manipulation by parties other than licensed chiropractors;
and

(vii) They incorrectly assume that patients undergoing adverse events
following a manipulation might not have reported such instances to
either the attending chiropractor or an appropriate authority.

Many signs point to intrinsic aberrations of
arterial structure underlying CVAs, many brought on by elevated levels of
homocysteine. When applied to cervical manipulations, the body of evidence
outlined in this discussion suggests that the inherent fragility of the
arterial wall of the cerebrovascular system rather than any trauma
associated with maneuvers by the attending physician is the major culprit
regarding arterial dissections. The determination of homocysteine levels as
a clinical tool would appear to afford the chiropractic physician a means to
bring the actual risks of CVAs to even lower levels than those previously
reported. In this regard, homocysteine determinations currently appear to be
the most plausible means for assessing patients who are most at risk for
experiencing CVAs from routine activities, let alone from cervical
manipulations. (With regard to the topics of spontaneous vertebral artery
dissections and the possible role of homocysteine as a proposed indicator of
patients at risk, I have published more detailed presentations elsewhere. [91,92])

The actual risk of CVAs that can be directly
attributable to spinal manipulation may be reduced to far less conspicuous
levels when compared to everyday lifestyle risks and those brought on by
medical treatments widely accepted by the public. Certainly the propagation
of risk estimates attributable to visits to the chiropractor’s office
without adequate justification from data does not perform a useful service
to the public; indeed, it does just the opposite. CVAs have been listed as
only the fifth most common cause of chiropractic malpractice
lawsuits, an unlikely ranking if chiropractors were conclusively found at
fault for the majority of CVAs reported. [90]

Type
of loss study: Malpractice only for loss year 1995. Des Moines, IA:
National Chiropractic Mutual Insurance Company as reported in
Jagbandhansingh, MP. Most common causes of chiropractic malpractice
lawsuits. Journal of Manipulative and Physiological Therapeutics
1997; 20(1): 60-64.